Src promotes EGF‐induced epithelial‐to‐mesenchymal transition and migration in gastric cancer cells by upregulating ZEB1 and ZEB2 through AKT

Abstract

Epithelial-to-mesenchymal transition (EMT) plays important roles in the migration, invasion, and metastasis of cancer cells. However, the role of Src in epidermal growth factor (EGF)-induced EMT and migration in gastric cancer cells remains to be clarified. In the current study, the effect of Src on EGF-stimulated EMT and migration was explored in gastric cancer cells. EGF induced EMT in gastric cancer cells and increased their migratory ability, which was accompanied by the phosphorylation of Src. PP2, the Src inhibitor, markedly suppressed EGF-mediated EMT and migration in gastric cancer cells. Additionally, EGF-stimulated upregulation of zinc finger E-box binding homeobox 1 (ZEB1) and zinc finger E-box binding homeobox 2 (ZEB2) was significantly repressed by PP2. Further analysis showed that EGF-stimulated phosphorylation of protein kinase B (AKT) was almost completely abolished by PP2, whereas that of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3) was only mildly suppressed. Moreover, LY294002, the AKT inhibitor, significantly inhibited EGF-induced upregulation of ZEB1 and ZEB2 as well as EMT and migration stimulated by EGF in gastric cancer cells. However, neither ERK inhibitor nor STAT3 inhibitor repressed EGF-induced EMT-related changes. Taken together, these results suggest that Src promotes EGF-stimulated EMT and migration by upregulation of ZEB1 and ZEB2 through AKT signaling pathway in gastric cancer cells.

CEP55 promotes epithelial–mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR pathway

“…Previous study showed that miR-200c suppresses the expression of ZEB1 through PI3K/AKT signaling pathway in non-small cell lung cancer [31]. Furthermore, Src promotes the process of EMT by upregulation of ZEB1 and ZEB2 through AKT signaling pathway in gastric cancer cells [32]. In addition, it has been reported that CEP55 binds to PI3K and increases the stability of this subunit, resulting in increased AKT activation as observed by an increase in S473 phosphorylation [33].…”

A Novel Model of Cancer Drug Resistance: Oncosomal Release of Cytotoxic and Antibody-Based Drugs

“…It was recently shown that the oncoprotein Src in endosomal membranes promoted exosome secretion and tumor progression [186]. Consistently, Src promotes EMT triggered by multiple EMT inducers including EGF [187], leptin [188], Cten [189], and δNp63γ [190]. Anti-EMT strategies involving targeting the TGFβ receptor or CDK2 may inhibit exosome/oncosome release from cancer cells [36].…”

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Nuclear interactions, as well as cytoplasmic interactions between EGFR and STAT3, increase the expression of iNOS, cyclin D1, and c-fos via direct binding of EGFR/STAT3 complex to their promoters [64]. Moreover, aberrant EGF/EGFR signaling enhances EMT and cisplatin-resistance through the activation of JAK2/STAT3 via the following: increasing IL-6 and LIF production [65], src-induced Zeb1 and Zeb2 upregulation [66], and increasing Twist-1 expression via binding of STAT3 to the promoter of Twist-1 [67,68]. PTK6 interacts with the EGFR family-including EGFR, HER2, HER3-and aggravates cancer through activation of RAS/MAPK, PI3K/AKT, and STAT3 [69].…”